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MBC in Press, published online ahead of print October 3, 2007
Mol. Biol. Cell 10.1091/mbc.E07-04-0368

A more recent version of this article appeared on December 1, 2007
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Submitted on April 24, 2007
Revised on September 21, 2007
Accepted on September 26, 2007

Synaptotagmin C2A Loop 2 Mediates Ca2+-dependent SNARE Interactions Essential for Ca2+-triggered Vesicle Exocytosis

K. L. Lynch,*{dagger} R. R.L. Gerona,*{dagger} E. C. Larsen,*{dagger} R. F. Marcia,*{ddagger} J. C. Mitchell,*{ddagger} and T. F.J. Martin*

Departments of *Biochemistry and {ddagger}Mathematics, University of Wisconsin, Madison, WI 53706

Monitoring Editor: Patrick Brennwald

Synaptotagmins contain tandem C2 domains and function as Ca2+ sensors for vesicle exocytosis but the mechanism for coupling Ca2+ rises to membrane fusion remains undefined. Synaptotagmins bind SNAREs, essential components of the membrane fusion machinery, but the role of these interactions in Ca2+-triggered vesicle exocytosis has not been directly assessed. We identified sites on synaptotagmin-1 that mediate Ca2+-dependent SNAP25 binding by zero-length cross-linking. Mutation of these sites in C2A and C2B eliminated Ca2+-dependent synaptotagmin-1 binding to SNAREs without affecting Ca2+-dependent membrane binding. The mutants failed to confer Ca2+ regulation on SNARE-dependent liposome fusion and failed to restore Ca2+-triggered vesicle exocytosis in synaptotagmin-deficient PC12 cells. The results provide direct evidence that Ca2+-dependent SNARE binding by synaptotagmin is essential for Ca2+-triggered vesicle exocytosis, and that Ca2+-dependent membrane binding by itself is insufficient to trigger fusion. A structure-based model of the SNARE-binding surface of C2A provided a new view of how Ca2+-dependent SNARE and membrane binding occur simultaneously.

{dagger}These authors contributed equally to this work.

Address correspondence to: T. F.J. Martin (tfmartin{at}wisc.edu)




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